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STK11c.129_141delLikely pathogenic
Print report
Variant interpretation report

STK11 c.129_141del, p.(Lys44SerfsTer3)

NM_000455.5:c.129_141del NP_000446.1:p.(Lys44SerfsTer3) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About STK11

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

NM_000455.5(STK11):c.129_141del is a 13bp frameshift deletion in exon 1 (of 9 coding exons) resulting in p.(Lys44SerfsTer3). STK11 loss of function is a well-established disease mechanism for Peutz-Jeghers syndrome (autosomal dominant). The premature termination codon at position 46 occurs well before the last exon-exon junction and is predicted to trigger nonsense-mediated decay, leading to complete absence of the STK11 protein product. Under ClinGen SVI PVS1 recommendations (PMC6185798), full-strength PVS1 is applicable.

PM2Moderate
PM2 · moderate

NM_000455.5:c.129_141del is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), consistent with a rare pathogenic variant. Under generic ACMG/AMP rules, absence from large population databases supports a pathogenic interpretation (PM2).

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 9 not met · 9 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000455.5(STK11):c.129_141del is a 13bp frameshift deletion in exon 1 producing p.(Lys44SerfsTer3), predicted to trigger nonsense-mediated decay and complete loss of STK11 protein expression. STK11 loss of function is a well-established mechanism for Peutz-Jeghers syndrome (autosomal dominant).

This variant is absent from gnomAD v2.1 and v4.1 population databases, consistent with a rare pathogenic variant.

The variant has not been reported in ClinVar, COSMIC, or any published patient cohort evaluated in this assessment.

No variant-specific functional studies, segregation data, or de novo observations were identified in the literature. Five OncoKB-curated STK11 publications were reviewed; none mention this variant.

Applying generic ACMG/AMP 2015 classification rules (PMID:25741868): PVS1 (very_strong) + PM2 (moderate) meets the Likely Pathogenic combination threshold (1 Very Strong + 1 Moderate).

Met · 2

PVS1 Very strongNM_000455.5(STK11):c.129_141del is a 13bp frameshift deletion in exon 1 (of 9 coding exons) resulting in p.(Lys44SerfsTer3). STK11 loss of function is a well-established disease mechanism for Peutz-Jeghers syndrome (autosomal dominant). The premature termination codon at position 46 occurs well before the last exon-exon junction and is predicted to trigger nonsense-mediated decay, leading to complete absence of the STK11 protein product. Under ClinGen SVI PVS1 recommendations (PMC6185798), full-strength PVS1 is applicable. Details ▾Hide ▴
Evidence considered
  • Frameshift (13bp deletion) in exon 1/9 of STK11
  • a tumor suppressor gene with established LOF mechanism in Peutz-Jeghers syndrome
  • Premature termination at codon 46 predicted to trigger NMD (PTC well upstream of last exon-exon junction)
  • Transcript NM_000455.5 is MANE select
  • variant absent from gnomAD population databases
Still missing
  • Exon 1 contains the start codon
  • confirm that no alternative downstream start codon could rescue expression
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
PM2 ModerateNM_000455.5:c.129_141del is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), consistent with a rare pathogenic variant. Under generic ACMG/AMP rules, absence from large population databases supports a pathogenic interpretation (PM2). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles)
  • Absent from gnomAD v4.1 (0 alleles)
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 9 · evaluated, threshold not reached

PS2 No de novo observation has been reported for NM_000455.5:c.129_141del. A de novo STK11 frameshift variant (c.698_699insG) has been reported in Peutz-Jeghers syndrome (PMID:22118009) but this is a different variant and does not constitute evidence for the variant under assessment. Details ▾Hide ▴
Still missing
  • No de novo testing data available for this specific variant
Sources
pvs1_gene_context
PM1 The variant at codon 44 is located N-terminal to the STK11 kinase domain (approximately residues 49-309). This residue is not in a statistically significant mutational hotspot and does not reside in a well-established critical functional domain with restricted mutational spectrum. Details ▾Hide ▴
Evidence considered
  • Not in a statistically significant hotspot (cancerhotspots.org)
  • Variant is N-terminal to the kinase domain
PM6 No de novo observation has been reported for this variant. Assumed de novo without confirmation of maternity/paternity is not applicable. Details ▾Hide ▴
Still missing
  • No de novo testing performed for this variant
PP5 No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar and has not been reported by any diagnostic laboratory. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
Sources
clinvar ↗
BA1 NM_000455.5:c.129_141del is absent from gnomAD v2.1 and v4.1. The allele frequency does not exceed the BA1 threshold (>1%). Details ▾Hide ▴
Evidence considered
  • Allele frequency: 0.0 (absent from gnomAD)
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 NM_000455.5:c.129_141del is absent from gnomAD v2.1 and v4.1. The allele frequency does not exceed the BS1 threshold (>0.3%). Details ▾Hide ▴
Evidence considered
  • Allele frequency: 0.0 (absent from gnomAD)
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 Computational evidence does not support a benign interpretation. The variant is a frameshift deletion predicted to produce a truncated protein (p.Lys44SerfsTer3) with complete loss of the kinase domain and C-terminal regulatory regions, consistent with a loss-of-function mechanism. SpliceAI scores are not meaningful for evaluating the protein-level effect of a frameshift. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta: 0.02 (no cryptic splicing
  • not informative for frameshift)
Sources
spliceai ↗
BP6 No reputable source has reported this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
Sources
clinvar ↗
PS5 No reputable germline source has reported this variant as pathogenic. OncoKB classification (Likely Oncogenic) reflects somatic/oncogenic context and is not a germline pathogenicity assertion. Details ▾Hide ▴
Sources
oncokb ↗

Not assessed · 9 · no assessment recorded

PS3 No variant-specific functional studies were identified for NM_000455.5:c.129_141del in the literature. The five OncoKB-curated papers discuss STK11/LKB1 function or structure at the gene level but do not mention this variant. OncoKB classifies this variant as Likely Oncogenic/Likely Loss-of-function, but this is a computational prediction based on variant type, not experimental functional evidence. Details ▾Hide ▴
Evidence considered
  • OncoKB predicts Likely Loss-of-function based on frameshift variant type
  • not experimental data
Still missing
  • No variant-specific functional assays (e.g.
  • kinase activity
  • protein expression
  • AMPK phosphorylation) identified
Sources
oncokb ↗
PS4 No case-control or prevalence data are available for this variant. The variant is absent from ClinVar and has not been reported in any published patient cohort. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
Still missing
  • No affected vs. control prevalence comparison possible
Sources
clinvar ↗
PP1 No cosegregation data are available for this variant. No family studies have been reported. Details ▾Hide ▴
Still missing
  • No family segregation data available
PP4 No patient phenotype or family history data were provided for clinical correlation. Details ▾Hide ▴
Still missing
  • Patient phenotype and family history not available for review
BS2 No observation of this variant in healthy adult individuals has been reported. Absence from gnomAD is consistent with rarity but does not constitute direct observation in a healthy control. Details ▾Hide ▴
Still missing
  • No healthy individual observation data
BS3 No variant-specific functional studies demonstrating a benign effect are available for NM_000455.5:c.129_141del. Details ▾Hide ▴
Still missing
  • No functional studies available for this variant
BS4 No family segregation data are available to evaluate lack of segregation with disease. Details ▾Hide ▴
Still missing
  • No segregation data available
BP2 No data on observation of this variant in trans with a pathogenic STK11 variant or in cis with a pathogenic variant are available. Details ▾Hide ▴
Still missing
  • No phase data available
BP5 No data identifying an alternate molecular basis for disease in a patient carrying this variant are available. Details ▾Hide ▴
Still missing
  • No alternate molecular diagnosis data
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to single-nucleotide substitutions at a codon where a different pathogenic amino acid change has been established. This is a 13bp frameshift deletion, not a nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions and stop-loss variants that alter protein length without a frameshift. This is an out-of-frame (frameshift) deletion assessed under PVS1. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 applies to novel missense variants at a codon where a different pathogenic missense change has been established. This is a frameshift deletion, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation where missense changes are a common disease mechanism. This is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

PP3 N/AFor frameshift/null variants where PVS1 is already applied at full strength, computational evidence of deleterious effect (PP3) is not additive. SpliceAI predicts no significant splice impact (max delta score 0.02), consistent with a variant whose pathogenicity is mediated through protein truncation rather than splicing. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score: 0.02 (no significant splice impact)
Sources
spliceai ↗
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. This is a truncating (frameshift) variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function. This is an out-of-frame (frameshift) deletion. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. This is a frameshift deletion, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
STK11
Transcript
NM_000455.5
Coding (HGVS c.)
NM_000455.5:c.129_141del
Protein (HGVS p.)
NP_000446.1:p.(Lys44SerfsTer3)
GRCh38
chr19:1207038 GGGCCAAGCTCATC>G
GRCh37
chr19:1207037 GGGCCAAGCTCATC>G

Gene diagram

Every interpreted variant in STK11, mapped onto the exon structure of NM_000455.5. Select a row to find it on the plot.

STK11NM_000455.5
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -457 bp
0.020
SpliceAI acceptor gainat -202 bp
0.020
SpliceAI donor lossat +169 bp
0.000
SpliceAI donor gainat +355 bp
0.000
Pangolin splice lossmagnitude shown
-0.050
Pangolin splice gain
0.030

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 Computational evidence does not support a benign interpretation. The variant is a frameshift deletion predicted to produce a truncated protein (p.Lys44SerfsTer3) with complete loss of the kinase domain and C-terminal regulatory regions, consistent with a loss-of-function mechanism. SpliceAI scores are not meaningful for evaluating the protein-level effect of a frameshift. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta: 0.02 (no cryptic splicing
  • not informative for frameshift)
Sources
spliceai ↗
PP3 N/AFor frameshift/null variants where PVS1 is already applied at full strength, computational evidence of deleterious effect (PP3) is not additive. SpliceAI predicts no significant splice impact (max delta score 0.02), consistent with a variant whose pathogenicity is mediated through protein truncation rather than splicing. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score: 0.02 (no significant splice impact)
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. This is a frameshift deletion, not a synonymous variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Somatic LKB1 mutations promote cervical cancer progression.
    Reports somatic LKB1 mutations in cervical cancer cell lines and primary tumors. NM_000455.5:c.129_141del was not identified in this paper.
    Does not name this variant
    PMID 19340305 ↗
  • Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation.
    Reports the crystal structure of the LKB1-STRAD-MO25 heterotrimeric complex and describes the allosteric mechanism of kinase activation. NM_000455.5:c.129_141del was not identified in this paper.
    Does not name this variant
    PMID 19892943 ↗
  • The role of LKB1 in lung cancer.
    Reviews the role of LKB1 in lung cancer, describing the spectrum of somatic LKB1 mutations including recurrent Q37X, 837-842delC, and frameshift indels at codons 51-53. NM_000455.5:c.129_141del was not identified in this paper.
    Does not name this variant
    PMID 21516316 ↗
  • STK11 domain XI mutations: candidate genetic drivers leading to the development of dysplastic polyps in Peutz-Jeghers syndrome.
    Reports STK11 mutation spectrum in 116 Chinese PJS patients, identifying 25 point mutations including a c.151_162del (p.M51_L54del) in exon 1. NM_000455.5:c.129_141del was not identified in this paper.
    Does not name this variant
    PMID 24652667 ↗
  • Comprehensive molecular profiling of lung adenocarcinoma.
    Reports comprehensive molecular profiling of 230 lung adenocarcinomas by TCGA, identifying STK11 as one of 18 significantly mutated genes. NM_000455.5:c.129_141del was not identified in this paper.
    Does not name this variant
    PMID 25079552 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.020 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.